Advanced cancer typically produces severe pain in patients. This pain is often controlled by the administration of large doses of analgesics, including opioid analgesics. However, the pain relief is often accompanied by undesirable side-effects such as unacceptable sedation and/or a decrease in cognitive function. These side effects have a significant negative impact on the quality of life of the patient. In addition, cancer patients often display one or more of a decrease in cognitive function, fatigue, and neurobehavioral slowing that is unrelated to the administration of analgesics, but may be related to the underlying cancer, the treatment of the cancer, or both.
Menopause is accompanied by several side effects, including an executive function defect. For example, many menopausal women report impairment in short term memory, inability to screen distractions and sustain attention in organization of thoughts and tasks. In addition, women diagnosed with ADD prior to menopause report exacerbation of ADD symptoms during the protracted perimenopausal period and thereafter. See Brown, T. E., Attention-Deficit Disorders and Comorbidities in Children, Adolescents and Aduts, American Psychiatric Press, Washington, D.C., 2000, at p. 40-41.
Methylphenidate has been used to treat nervous system disorders including Attention Deficit Disorder (ADD), a commonly diagnosed nervous system illness in children, Attention Deficit Hyperactivity Disorder (ADHD), and cognitive decline in patients with Acquired Immunodeficiency Syndrome (AIDS) or AIDS related conditions. See, e.g., Brown, G., Intl. J. Psych. Med. 25(1): 21-37 (1995); Holmes et al., J. Clin. Psychiatry 50: 5-8 (1989). The racemic form of methylphenidate also has been proposed to improve cognitive function in patients receiving large doses of medication. See, for example, Bruera et al., Pain (1992) 163-166, Yee et al., Journal of Pain and Symptom Management (1994), Vol. 9, No.2, 122-125, and Meyers et al., Journal of Clinical Oncology (1998) Vol. 16, No. 7, 2522-2527.
Methylphenidate exists as four separate optical isomers as follows: wherein R2 is phenyl. Pharmaceutically acceptable salts are generally administered clinically. Other phenidate drugs, which also can be administered according to the invention, include those in which the methyl group in the above structures is replaced by C2-4 alkyl and those in which R2 is optionally substituted with C1-4 alkyl.
Clinically, the threo pair of enantiomers of methylphenidate hydrochloride is generally administered for the treatment of ADD and ADHD. The hydrochloride salt is commonly referred to simply as “methylphenidate”. Unless indicated otherwise, the term “methylphenidate” is used broadly herein to include methylphenidate and pharmaceutically acceptable salts thereof, including methylphenidate hydrochloride.
The threo racemate (pair of enantiomers) of methylphenidate is a mild central nervous system stimulant with pharmacological activity qualitatively similar to that of amphetamines. Undesirable side effects associated with the use of the DL-threo racemate of methylphenidate include anorexia, weight loss, insomnia, dizziness and dysphoria. Furthermore, the racemate, which is a Schedule II controlled substance, produces a euphoric effect when administered intravenously or through inhalation or ingestion, and thus carries a high potential for abuse.
Srinivas et al. studied the administration of DL-threo-, D-threo, and L-threo-methylphenidate to children suffering from ADHD, and reported that the pharmacodynamic activity of DL-threo-methylphenidate resides in the D-threo isomer (Clin. Pharmacol. Ther., 52: 561-568 (1992)). While DL-threo-methylphenidate is generally used therapeutically, this racemate includes the L isomer which apparently makes no significant contribution to the pharmacological effectiveness of the drug. The removal of the L isomer is expensive, however, and there has been no reason to do so.
It has been discovered that the use of the D-threo isomer (2R:2′R) of methylphenidate, substantially free of the 1-threo isomer, produces a methylphenidate medication which retains high activity levels and simultaneously may possess reduced euphoric effect and reduced potential for abuse among patients. See U.S. Pat. Ser. No. 5,908,850, incorporated herein by reference in its entirety. Thus, D-threo-methylphenidate (2R:2′R) may possesses enhanced therapeutic activity with reduced side effects, and 1-threo-methylphenidate may produce undesirable side effects, euphoria and drug abuse potential in patients.
There remains a need for improved methods for alleviating the undesirable symptoms and side-effects described above. This invention is directed to these, as well as other, important ends.